Abstract:
:Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to further explore the opportunity of "designing in" halogen bonding interactions in structure-based ligand design for the 5-HT2B receptor, which not only facilitated the identification of previously uncharacterized halogen bonds in known 5-HT2B ligands but also enabled the rational design of halogen bonding interactions for the optimization of 5-HT2B ligands. As a proof-of-concept, a series of halogen-substituted analogues of doxepin was synthesized and evaluated, which showed improved in vitro and in vivo potency.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Zhou Y,Wang Y,Li P,Huang XP,Qi X,Du Y,Huang Ndoi
10.1021/acsmedchemlett.8b00300subject
Has Abstractpub_date
2018-10-01 00:00:00pages
1019-1024issue
10issn
1948-5875journal_volume
9pub_type
杂志文章abstract::A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00189
更新日期:2019-06-24 00:00:00
abstract::Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00014
更新日期:2017-03-01 00:00:00
abstract::Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinas...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400206q
更新日期:2013-08-12 00:00:00
abstract::Specific abrogation of cyclin-dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screening was employed to identify novel scaffolds from a library of com...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00029
更新日期:2019-03-20 00:00:00
abstract::A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be dis...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00040
更新日期:2020-05-18 00:00:00
abstract::Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. T...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00173
更新日期:2018-07-02 00:00:00
abstract::Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00013
更新日期:2017-02-16 00:00:00
abstract::Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not ind...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5004475
更新日期:2014-12-12 00:00:00
abstract::The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for developme...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1001689
更新日期:2011-03-10 00:00:00
abstract::Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00568
更新日期:2020-03-30 00:00:00
abstract::To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00455
更新日期:2016-01-04 00:00:00
abstract::The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300147m
更新日期:2012-08-28 00:00:00
abstract::Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar r...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4004556
更新日期:2014-01-10 00:00:00
abstract::Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the la...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00037
更新日期:2015-03-04 00:00:00
abstract::A series of fluorine-substituted monomeric and dimeric cRGD peptide derivatives, such as cRGD-ADIBOT-F (ADIBOT = azadibenzocyclooctatriazole), di-cRGD-ADIBOT-F, cRGD-PEG5-ADIBOT-F, and di-cRGD-PEG5-ADIBOT-F, were prepared by strain-promoted alkyne azide cycloaddition (SPAAC) reaction of the corresponding aza-dibenzocy...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500464f
更新日期:2015-02-06 00:00:00
abstract::Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4003309
更新日期:2014-01-30 00:00:00
abstract::Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include th...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400292s
更新日期:2013-11-20 00:00:00
abstract::The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ε-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual k...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00227
更新日期:2019-08-02 00:00:00
abstract::A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust ph...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500440u
更新日期:2015-05-07 00:00:00
abstract::A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crysta...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300237v
更新日期:2012-10-24 00:00:00
abstract::Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's M...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00558
更新日期:2019-02-07 00:00:00
abstract::The solution behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00162
更新日期:2017-09-06 00:00:00
abstract::Bacterial RNA polymerase (RNAP) is essential for transcription and is an antibacterial target for small molecule inhibitors. The binding region of myxopyronin B (MyxB), a bacterial RNAP inhibitor, offers the possibility of new inhibitor design. The molecular design program SPROUT has been used in conjunction with the ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200087m
更新日期:2011-07-29 00:00:00
abstract::Computer-aided drug design could benefit from a greater understanding of how errors arise and propagate in biomolecular modeling. With such knowledge, model predictions could be associated with quantitative estimates of their uncertainty. In addition, novel algorithms could be designed to proactively reduce prediction...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4002634
更新日期:2013-09-12 00:00:00
abstract::In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00485
更新日期:2020-12-09 00:00:00
abstract::Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5003234
更新日期:2014-10-29 00:00:00
abstract::Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desm...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200254h
更新日期:2012-03-08 00:00:00
abstract::SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100016x
更新日期:2010-03-15 00:00:00
abstract::Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00081
更新日期:2018-04-16 00:00:00
abstract::Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, whi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500494j
更新日期:2015-01-28 00:00:00